Fasting as an Adjuvant Therapy for Cancer: Mechanism of Action and Clinical Practice

Abstract

The fundamental biological characteristics of tumor cells are characterized by irregularities in signaling and metabolic pathways, which are evident through increased glucose uptake, altered mitochondrial function, and the ability to evade growth signals. Interventions such as fasting or fasting-mimicking diets represent a promising strategy that can elicit distinct responses in normal cells compared to tumor cells. These dietary strategies can alter the circulating levels of various hormones and metabolites, including blood glucose, insulin, glucagon, growth hormone, insulin-like growth factor, glucocorticoids, and epinephrine, thereby potentially exerting an anticancer effect. Additionally, elevated levels of insulin-like growth factor-binding proteins and ketone bodies may increase tumor cells' dependence on their own metabolites, ultimately leading to their apoptosis. The combination of fasting or fasting-mimicking diets with radiotherapy or chemotherapeutic agents has demonstrated enhanced anticancer efficacy. This paper aims to classify fasting, elucidate the mechanisms that underlie its effects, assess its impact on various cancer types, and discuss its clinical applications. We will underscore the differential effects of fasting on normal and cancer cells, the mechanisms responsible for these effects, and the imperative for clinical implementation.

Keywords: cancer; cellular autophagy; clinical applications; energy restriction; fasting; metabolism.

Figure 1

Classification of fasting and its functions. IF is a method of energy deprivation during regular periods of very limited or no calorie intake, i.e., periods of voluntary food and water fasting. It usually includes a 16 h daily fast, a 24 h fast every other day, or two non-consecutive days of fasting per week. TRF is a form of dietary restriction that limits the time spent eating to less than 10 h per day without reducing the overall daily calorie intake. CR is a reduction in the average daily calorie intake by 20–40% without causing malnutrition or deficiencies in essential nutrients. The FMD is characterized by a low-calorie, low-protein, and high-fat nutritional approach that aims to replicate the metabolic effects associated with fasting while permitting a restricted consumption of food. Despite differences in definitions and molecular mechanisms and signaling regulation, the benefits and mechanisms of fasting have been linked to the regeneration and differentiation of a wide range of tissues and cells, including brain neurogenesis, and the regeneration of NK cells, T cells, and B cells. In addition to this, fasting enhances the host’s anti-tumor immune response and mitochondrial function, renews the gut microbiota, and enhances autophagy to remove body waste and perform DNA repair.

Figure 2

Differences in body metabolic indices between subjects with metabolic syndrome and fasting subjects. (A) Metabolic syndrome is a pathological state in which the metabolism of proteins, fats, and carbohydrates is disturbed in the human body, and it is a group of complex metabolic disorder syndromes that are risk factors for diabetes mellitus and cardiovascular and cerebrovascular diseases. Changes in metabolite levels have been detected in patients with metabolic syndrome: Adiponectin is decreased; Leptin, IL-1β, IL-6, TNFα, RBP4, lipocalin, resisting, PEDF, vastatin, omentin, chemerin, advising, and ASP are increased. Macrophages recruit MCP1, MlP1α, and CXCL5. (B) Fasting subjects undergo changes in systemic metabolic levels after a fasting analog diet. The blood pressure and resting heart rate of the cardiovascular system decreased; parasympathetic tone and stress increased. Cognitive ability, neurotrophic factor production, synaptic plasticity, mitochondrial biogenesis, resistance to disease, and inflammation were increased and reduced in the brains of fasted subjects. Blood glucose, insulin, leptin, total cholesterol, CRP, TNFα, IL-6, markers of oxidative stress, and lGF-1 decreased; 30 HB and adiponectin increased. In the liver, glycogen depletion, ketone production, increased insulin sensitivity, and reduced lipid accumulation were observed. In addition, fasting reduced intestinal inflammation. Overall, fasting resulted in increases in anticancer serum proteomic signatures, DNA repair proteins, key regulatory proteins involved in insulin signaling and insulin sensitivity, and proteins associated with prolonged longevity. At the same time, fasting decreased subjects’ weight, body mass index, waist circumference, systolic and diastolic blood pressure, and insulin resistance.

Figure 3

Mechanisms by which fasting or fasting-mimicking diets kill cancer cells in solid tumors. Preclinical and preliminary clinical data suggest that fasting or FMDs reduce levels of nutrients and factors that promote tumor growth, including glucose, IGF1, and insulin, and enhance autophagy. Fasting is involved in the TCA cycle through the production of lactate from GLUT and aerobic glycolysis, and carbon dioxide from TCA is involved in mitochondrial function. Reducing glucose uptake and forcing cancer cells to increase OXPHOS, ROS, ΔΨm loss, and ADP/ATP induce an anti-Warburg effect, which leads to oxidative DNA damage, p53 activation, DNA damage, and cell death, especially during chemotherapy. Fasting or fasting-mimicking diets act on the AMPK signaling pathway via IGF1 and activate the organismal autophagy pathway via P62 and LC3II. Fasting or fasting analog diets can reduce CD73 levels in certain cancer cells by activating autophagy, thereby attenuating adenosine production in the extracellular milieu and preventing the transition of macrophages to an immunosuppressive M2 phenotype. Notably, fasting or fasting-mimicking diets can have very different or even opposite effects in different cancer cell types, or even in the same cancer cell type.